Compelling evidence suggests that genes linked to coronary artery disease (CAD) can be identified in Mexican Americans (MA) using insulin resistance (IR), hyperinsulinemia and components of the IR syndrome as intermediate phenotypes for CAD. Our data in MA offspring of parents with CAD indicate that 1) carotid intimal medial wall thickness (IMT), a subclinical measure of atherosclerosis and IR are highly heritable in MA and share common genes and 2) IR predicts IMT. Thus, the IR syndrome is likely a primary cause of CAD in this growing ethnic group. We hypothesize that there is a strong genetic basis for IR, components of the IR syndrome, and CAD; that they share common genes; and that IR and the metabolic syndrome are major contributing factors to CAD in MA. Specific aims: 1) Phenotype and obtain DNA from 1250 MA offspring (900) with at least one parent affected with CAD and spouses (350) of the offspring. Phenotyping will emphasize IR and associated factors; measurements of apolipoproteins and paraoxonase (which may predict or contribute to CAD and may be related to the IR syndrome); and assessment of subclinical atherosclerosis by carotid intimal-medial wall thickness (IMT). 2) Analyze physiologic interrelationships among these traits and their relationships to CAD in MA in order to dissect a more homogeneous syndrome associated with IR and identify determinants of CAD 3) Assess familiality, common gene effects, and heterogeneity of the phenotypes by genetic analyses of the measured quantitative traits. This proposal represents the first family study to determine insulin action directly by euglycemic clamp and to ascertain based on the presence of documented CAD. We will measure of apolipoproteinJ/paraoxonase ratio which is a novel marker for CAD and which may regulate oxidation of low density lipoprotein (LDL) cholesterol. This detailed and unprecedented phenotyping will 1) reveal important physiologic and genetic relationships which impact on structural changes in the vasculature critical to the atherosclerotic process, 2) maximize the power to identify gene linkages (as described in Project 2), and 3) ultimately contribute to the development of more targeted approaches to prevent and treat CAD in the setting of insulin resistance.